Adenosine receptors and caffeine in retinopathy of prematurity

Abstract

Retinopathy of prematurity (ROP) is a major cause of childhood blindness in the world and is caused by oxygen-induced damage to the developing retinal vasculature, resulting in hyperoxia-induced vaso-obliteration and subsequent delayed retinal vascularization and hypoxia-induced pathological neovascularization driven by vascular endothelial growth factor (VEGF) signaling pathway in retina. Current anti-VEGF therapy has shown some effective in a clinical trial, but is associated with the unintended effects on delayed eye growth and retinal vasculature development of preterm infants. Notably, cellular responses to hypoxia are characterized by robust increases in extracellular adenosine production and the markedly induced adenosine receptors, which provide a novel target for preferential control of pathological angiogenesis without affecting normal vascular development. Here, we review the experimental evidence in support of adenosine receptor-based therapeutic strategy for ROP, including the aberrant adenosine signaling in oxygen-induced retinopathy and the role of three adenosine receptor subtypes (A1R, A2AR, A2BR) in development and treatment of ROP using oxygen-induced retinopathy models. The clinical and initial animal evidence that implicate the therapeutic effect of caffeine (a non-selective adenosine receptor antagonist) in treatment of ROP are highlighted. Lastly, we discussed the translational potential as well therapeutic advantage of adenosine receptor- and caffeine-based therapy for ROR and possibly other proliferative retinopathy.

Caffeine exposure ameliorates acute ischemic cell death in avian developing retina

“…Premature birth and low birth weight are the most significant risk factors for retinopathy of prematurity (ROP), one of the major causes of infant blindness [91]. Interestingly, it seems that caffeine can also help preventing this pathology progression [91,92]. Caffeine and the A 2A adenosine receptor have been investigated in the context of ROP.…”

Oxidative phosphorylation inducers fight pathological angiogenesis

“…Some of these compounds also appear to be beneficial for angiogenesis-related diseases. For example,caffeine [71,72]; polyphenols, such as curcumin, epigallocatechin gallate, quercetin, and resveratrol [73][74][75][76]; thiazolidinediones, such as rosiglitazone [77,78]; valproic acid [79,80]; D 9tetrahydrocannabinol [81,82]; and v3-polyunsaturated fatty acids, such as docosahexaenoic or eicosapentaenoic acids [83]. These compounds could be used, along with other antiangiogenic drugs, as adjuvants for either all patients with angiogenesis-related diseases or those belonging to a particular mtDNA haplogroup with a high genetic risk.…”

Caffeine: an evidence-based success story in VLBW pharmacotherapy

“…Adenosine subtype receptors in the retina modulate inflammation, neuroprotection, and angiogenesis, and a therapeutic benefit of caffeine for ROP appears to be supported by its ability to control angiogenic factors such as hypoxia inducible factor-1α and vascular endothelial growth factor (VEGF), angiogenesis, apoptosis of endothelial cells, and other vascular actions. 59,60 In a rat pup model of ROP, both caffeine and a non-steroidal anti-inflammatory drug given alone reduced retinal neovascularization, but when given together, appeared to prevent severe retinopathy related to effects on retinal and serum growth factors, including insulin-like growth factor-1 and VEGF. 61 Patent ductus arteriosus In the CAP Trial, caffeine-treated infants required less pharmacologic intervention for patent ductus arteriosus (PDA) closure compared with placebo-treated infants (29% vs. 38%, p < 0.001).…”